The objective of this proposal is to design and synthesize angiotensin analogs to specifically interact with either the metabolic enzymes and/or tissue receptors of the renin/angiotensin system. As regards metabolic enzymes our efforts will be directed towards development of specific and potent renin and converting enzyme inhibitors as well as synthesis of analogs resistant to degradative enzymes. Competitive antagonists at the receptor level will also be prepared. When possible, analogs capable of interacting at both the level of the enzymes involved and at receptor level will be prepared -that is we will prepare multi-functional antagonists capable of inhibiting at two or more points in the system. Other analogs will be synthesized to facilitate our continuing studies on the problem of angiotensin/receptor interactions in general and angiotensin tachyphylaxis specifically. These will include synthesis of radiolabelled (3H or 125I) angiotensin as well as some other labelled analogs. Synthesis of peptides will be primarily by solid-phase peptide synthesis although classical peptide synthesis will be utilized for specific analogs. Standard enzyme assays are available for renin and converting enzyme and a variety of bioassays are currently available to evaluate antagonists. These include rat uterus, guinea pig ileum, rabbit aortic strips and in vivo blood pressure (normotensive as well as Goldblatt and low Na+ hypertensive models). Receptor/ligand interactions will be studied by radioreceptor assay in subcellular fractions of uterus, aorta and possibly cardiac muscle.